There is a very large and rapidly growing unmet need for disease-modifying drugs for Alzheimer's disease (AD) as its prevalence is increasing worldwide due to demographic shifts in the aging population. AD is the third most costly disease in the US with direct costs over $200 billion annually. The proposed phase IIB program is for the continued development of small molecule drugs specifically inhibiting tau aggregation at the earliest steps of tau monomer self-association into oligomers that were discovered during the phase II program. A decrease in tau oligomer accumulation in neurons should also inhibit the formation of higher order aggregates. These drugs may also be effective in reducing extracellular tau oligomers that are not irreversibly linked. A decrease of tau oligomers in the extracellular compartment holds promise to eliminate the associative impairment of memory formation and the propagation of pathology to healthy neighboring neurons. Therefore, it is anticipated that therapeutic intervention that diminishes extracellular tau oligomers should lead to both an improvement in memory and a slowing or arresting of disease progression in AD patients. Symptomatic improvement in memory may be used as an early indication of drug efficacy in preclinical and clinical studies. In Phase II of the project, the assay was converted t a high throughput compound-screening platform, validated, and used to screen a diverse compound library. Antibody fragments for tau oligomers were selected and cloned (Tian et al. 2012). The proposed phase IIB program Specific Aims are: Perform secondary screen in cell assays for inhibition of tau oligomer accumulation Improve the potency of selected compounds in the primary and secondary assays Validate the tau oligomer target in an acute mouse model of memory formation Select compounds in the acute mouse model for testing in a chronic tauopathy model Develop regulatory strategy The anticipated outcome of the proposed Phase IIB program is the selection of at least three or more lead candidate compounds targeting tau oligomers for evaluation in animal models of AD and tauopathies. To attain this result, secondary screening in cell models of tau oligomer formation and medicinal chemistry will be used to optimize and select compounds for testing in the acute mouse model of tau-induced memory dysfunction. Following validation of the model for the tau oligomer target, selected active compounds will be screened and candidates chosen for further development. At the conclusion of the proposed program, a detailed regulatory strategy will be written to guide preclinical up to the IND submission and Ph 1 clinical trials. Key Words: Alzheimer's disease, tauopathy, neurodegenerative disease, drug discovery, tau, oligomer, cell model, mouse model, memory